Inhibition of polyamine oxidase improves the antitumoral effect of ornithine decarboxylase inhibitors.

Specific inhibition of ornithine decarboxylase activity prevents the formation of putrescine from ornithine and decreases spermidine levels of slow-growing organs by about 20%. However, spermidine levels of rapidly growing tissues, such as tumors, may under the same conditions be decreased by as much as 60%. Inactivation of polyamine oxidase prevents oxidative splitting of N1-acetylspermidine and N1-acetylspermine and therefore the reutilization of putrescine for de novo polyamine biosynthesis. Prolonged inhibition of ornithine decarboxylase and polyamine oxidase activities leads in all normal tissues studied so far to a decrease of the spermidine concentration by 50% or more, demonstrating the general physiological significance of polyamine reutilization. In this work the role of polyamine reutilization in tumors was studied. Combined treatment with the inhibitors of ornithine decarboxylase, alpha-difluoromethylornithine or (2R, 5R)-6-heptyne-2,5-diamine, and N1, N4-bis-allenylputrescine, an inhibitor of polyamine oxidase, produced a more marked depletion of the polyamine contents of L1210 ascitic cells and of Lewis lung carcinoma, than treatment with either compound alone. Concomitantly, the proliferative activity of these tumors decreased significantly below the value that was observed after treatment with an ornithine decarboxylase inhibitor alone. Our results demonstrate that polyamines which are produced by the interconversion pathway are used by the tumors in order to cover their polyamine requirement.